Antimicrobial composition and method of forming

Abstract

Disclosed herein is a composition that contains a polyhexamethylene guanidine salt and a thermoplastic polymer. The polyhexamethylene guanidine salt is grafted to the thermoplastic polymer. The present invention also relates to a method of forming the composition and to a mixture that can be beneficially employed to form the composition. The present invention also relates to medical devices comprising or consisting of said composition or from said mixture.

Description

[0001] ANTIMICROBIAL COMPOSITION AND METHOD OF FORMING

[0002] Technical field

[0003] The present invention relates to a composition that contains a polyhexamethylene guanidine salt and a thermoplastic polymer. The present invention also relates to a method of forming the composition and to a mixture that can be beneficially employed to form the composition. The present invention also relates to medical devices comprising or consisting of said composition or from said mixture.

[0004] Several problems are prevalent when implanting items in the human body. These problems include infection, formation of biofilms, and improper integration of the implant into the bone tissue.

[0005] It is common to coat medical devices for protection of the underlying medical devices material, to improve the properties of the medical device at the outer surface, or to impart a desired effect, such as anti-microbial effect.

[0006] Indeed, many current solutions for developing antimicrobial medical devices involve the addition of antibiotics or antiseptic molecules either directly into the medical device or via surface coatings. However, the biological fate of the eluted antimicrobials is difficult to predict and control. This can lead to systemic exposure, toxicity, and the development of antimicrobial resistance.

[0007] Furthermore, depending on the type of medical device, the latter can be subjected to large functional loads and shear stresses. In the cases where a coating is used there are challenges with coating integrity such as delamination and release of occlusive particles with potentially serious consequences in terms of vascular blockage.

[0008] In addition to that, during processing of said medical devices, cooling water is often used as the heat sink in melt processing of thermoplastics. However, when incorporating other components in the melt formulation of the thermoplastic polymer there is a danger that these components or additives are also soluble in the cooling water. This results in reduced concentrations of the additive in the polymer blend and contamination of the cooling water. This issue presents associated downstream challenges with wastewater disposal or remediation and in the case of an antimicrobial material there is also the risk of aquatoxicity.

[0009] Given these concerns, there is strong rationale for pursuing approaches that do not rely on discrete coatings or antimicrobial elution. Instead, contact-kill technologies — which immobilize antimicrobial functionality directly onto the device surface — offer a more stable and potentially safer alternative. These systems maintain antimicrobial efficacy without releasing agents into surrounding tissues, thereby minimizing systemic risks. However, achieving a durable surface capable of sufficient and prolonged contact-kill functionality without unduly sacrificing the mechanical properties of the medical device, and without costly or complicated surface modification techniques, has been difficult to achieve.

[0010] It would also be desirable for the system to be compatible with biomedical polyurethanes, which are widely preferred for medical devices such as catheters due to their unique combination of biocompatibility, mechanical versatility, and processability. Particularly thermoplastic polyurethanes (TPUs), offer a balance of flexibility and strength that is desired for devices navigating the body’s delicate pathways. TPUs are highly resistant to wear and chemical degradation. Furthermore, polyurethanes can be easily processed by extrusion or injection molding and their molecular structure can be engineered to achieve a wide range of hardness.

[0011] In Rogalsky et al. New promising antimicrobial material based on thermoplastic polyurethane modified with polymeric biocide polyhexamethylene guanidine hydrochloride. Materials Chemistry and Physics, 2021 , 267, pp.124682. 10.1016 / j.matchemphys.2021.124682, hal-03326565, polyurethane films are formed by a solvent casting method. Thermogravimetric analysis shows promising stability for melt processing and high antimicrobial efficacy is observed. However, this antimicrobial efficacy is as a result of large biocide release ratios of 28% to 48% after 50 hours immersion in water. This release indicates that the polyhexamethylene guanidine hydrochloride is not well-complexed into the polyurethane and will substantially leach antiseptic molecules in vivo.

[0012] Recognizing that eluting antimicrobials may be hazardous to human health, US2021 / 0277231 discloses a thermoplastic polyurethane that can be modified with a deprotonated guanidine compound covalently bonded into the polymeric backbone and a protonated guanidine compound hydrogen-bonded to the polymeric backbone. The preferred guanidine compounds are deprotonated or protonated PHMB (polyhexamethylene biguanide). The examples are extruded into tubing and are reported as showing good antimicrobial and non-fouling performance.

[0013] Zhang et al. in “Synthesis and antimicrobial activity of polymeric guanidine and biguanidine salts,” Polymer 40, 6189-6198 (1999) report good antimicrobial contact killing efficacy and heat stability from both polyhexamethylene guanidine salts and polyhexamethylene biguanidine salts. However, polyhexamethylene guanidine salts show superior results to polyhexamethylene biguanidine salts in a test of minimal inhibitory concentration. Polyhexamethylene biguanidine (PHMB) salts may also be less desired as having increased rate of sensitization. PHMB is also more expensive than polyhexamethylene guanidine (PHMG) salts, making PHMG salts the superior choice for medical devices. However, the inventors know of no suitable commercial solution for an antimicrobial medical-grade thermoplastic polymers, preferably polyurethane, comprising grafted, non-eluting PHMG salts. Despite existing solutions, there is a need for a medical device material that prevents bacterial adhesion and proliferation while withstanding shear and tensile stress loads, and at a suitable cost to performance ratio.

[0014] Summary

[0015] The present invention relates to a process for preparing a composition that contains a polyhexamethylene guanidine salt and a thermoplastic polymer. Indeed, it has been found that compounding a polyhexamethylene guanidine salt and a thermoplastic polymer as described herein provides a material that shows not only antimicrobial properties but also improved mechanical properties.

[0016] Therefore, a first aspect of the present invention is a process for preparing a composition comprising the steps of: a) providing an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form, b) mixing the antimicrobial polymer of step a) and at least a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof, and c) shaping the mixture obtained in step b).

[0017] It should be understood that during the preparation of the composition (also known as compounding), the antimicrobial polymer is covalently bonded to the thermoplastic polymer.

[0018] Indeed, under these conditions, the antimicrobial polymer is grafted into the thermoplastic polymer and provides benefits to downstream processing when the compounded composition is extruded or thermally processed into specific shapes. Finally, it addresses the requirement to provide an antimicrobial effect without leaching.

[0019] Brief Description of the Figures

[0020] Figure 1 is a 1 H-NMR spectrum of the polyhexamethylene guanidine hydrochloride salt. Figure 2 is a 1 H-NMR spectrum of extrudate from the compounding experiment in example 2 that was collected in water.

[0021] Figure 3 is a 1 H-NMR spectrum of the dry pellets obtained after the cutting step (from example 2).

[0022] Figure 4 is a composite of images showing the improved performance of a dry blend of PHMG-HCI and thermoplastic polyurethane (TPU) powders over powders mixed in separate hoppers at the extruder.

[0023] Detailed Description

[0024] In an embodiment, a composition comprises an antimicrobial polymer grafted onto a thermoplastic polymer. The antimicrobial polymer comprises a polyhexamethylene guanidine salt. Preferably, the antimicrobial polymer consists of a polyhexamethylene guanidine salt. Preferably the polyhexamethylene guanidine salt is dried before mixing with the thermoplastic polymer,

[0025] According to the invention, the polyhexamethylene guanidine salt in step a) is in a dry powder form. The dry powder form can be obtained according to different ways. Polyhexamethylene guanidine salt may be obtained in a powder form commercially or can be synthesized. The polyhexamethylene guanidine salt in a powder form is preferably submitted to additional drying prior to use. Another way to obtain the polyhexamethylene guanidine salt in a dry powder form is to dry an aqueous solution of polyhexamethylene guanidine salt.

[0026] The drying step (from the solid product or from the aqueous form) is preferably performed at a temperature comprised between 20 and 95 °C, more preferably between 30 and 75 °C and preferably under vacuum (pressure comprised between 5 mbar and 500 mbar, preferably between 5 and 250 mbar).

[0027] According to an embodiment, the polyhexamethylene guanidine salt is in a dry powder form and has an amount of water less than 300 ppm.

[0028] According to an embodiment, the polyhexamethylene guanidine salt is in a dry powder form and has an amount of water less than 200 ppm.

[0029] According to an embodiment, the polyhexamethylene guanidine salt is in a dry powder form and has an amount of water less than 100 ppm.

[0030] The water content can be easily determined by a person skilled in the art using known techniques, such as Karl Fisher titration.

[0031] Milling or grinding may be required to reach the appropriate powder size, shape, and uniformity. The polyhexamethylene guanidine salt in a dry powder form has preferably a particle size less than 10 mm, preferably less than 9 mm, preferably less than 8 mm, preferably less than 7 mm, preferably less than 6 mm, preferably less than 5 mm, preferably less than 4 mm, preferably less than 3 mm, preferably less than 2 mm.

[0032] Particle size is measured as any particles that pass through a given particle size sieve. As an example, particle size of less than 2 mm is measured as any particles that pass through 2 mm (2 mm x 2 mm square, or 2 mm diagonal) sieve.

[0033] Composition

[0034] The composition of the present invention can be in the form of pellets. The size can of the composition can vary from 0.5 to 5 mm.

[0035] Polyhexamethylene guanidine salt

[0036] According to an embodiment, the polyhexamethylene guanidine salt comprises a chloride, iodide, bromide, fluoride, phosphate (P04), sulfonate, carboxylate, or stearate salt. In an embodiment, the polyhexamethylene guanidine salt is chosen from the group consisting of chloride, iodide, bromide, fluoride, phosphate (PO4), sulfonate, carboxylate, stearate, and mixtures thereof.

[0037] According to a particular embodiment, the polyhexamethylene guanidine salt comprises polyhexamethylene guanidine hydrochloride salt (PHMG-HCI). In an embodiment, the polyhexamethylene guanidine salt consists of polyhexamethylene guanidine hydrochloride salt.

[0038] Thermoplastic polymer

[0039] The thermoplastic polymer of the present invention is polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof.

[0040] In an embodiment, the thermoplastic polymer of the present invention is polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, styrene-ethylene-butylene-styrene (SEBS) copolymer, and mixtures thereof.

[0041] The thermoplastic polymer is preferably in a powder or pellet form when combined with the antimicrobial polymer. In an embodiment, the thermoplastic polymer is present as a powder. In an embodiment, the thermoplastic polymer powder has preferably a particle size less than 10 mm, preferably less than 9 mm, preferably less than 8 mm, preferably less than 7 mm, preferably less than 6 mm, preferably less than 5 mm, preferably less than 4 mm, preferably less than 3 mm, preferably less than 2 mm.

[0042] A thermoplastic polymer is known to be a polymer that can be softened through heating before being processed and then left to cool and harden.

[0043] The thermoplastic polymer of the present invention is preferably biocompatible. A biocompatible polymer is biologically compatible by not producing a toxic, injurious, or immunologic response when in contact with living tissue. The thermoplastic polymer is also preferably biostable. A biostable polymer is one that substantially retains its structural integrity, mechanical performance, and chemical composition when exposed to physiological conditions, including bodily fluids and tissues, over an extended period.

[0044] According to a particular embodiment, the thermoplastic polymer is polyurethane.

[0045] “Polyurethane” and “polyurethane elastomers” are used interchangeably in the present invention. The abbreviation TPU refers to a thermoplastic polyurethane.

[0046] Polyurethane elastomers are typically block copolymers (also called segmented copolymers). Block copolymers are polymers comprising blocks (also called segments) of polymers (including oligomers) that are chemically distinct, and which show different thermal and mechanical properties, and different solubilities. Often the blocks in a block copolymer comprising two (or more) types of blocks are referred to as being 'hard’ and ‘soft’ polymer blocks, such different blocks resulting in microphase separation of hard and soft blocks. The hard block in a block copolymer typically comprises a rigid or high modulus polymer, with a melting temperature (Tm) or a glass transition temperature (Tg) higher than the use temperature, of e.g. about 35 °C. The soft block in the block copolymer often comprises a flexible, low modulus, amorphous polymer with a Tglower than 25 °C, preferably lower than 0 °C. As for most mechanical properties, thermal parameters like Tmand Tgare generally determined on dry samples; using well-known techniques like DSC or DMA. In such phase-separated block copolymers, the hard segments function as physical crosslinks for the flexible soft segments, resulting in materials having properties ranging from fairly stiff to flexible and elastic, depending on the ratio of hard to soft blocks. Depending on type and amount of hard blocks, the polyurethane may show good stability and elasticity over a desired temperature range without the need for chemical crosslinking; and can generally be processed as a thermoplastic.

[0047] The term thermoplastic polyurethane elastomer or TPU basically denotes a family of polymers with a backbone comprising the reaction product of at least three principle components; that are a diisocyanate, a diol chain extender and a polymer diol, and optionally a monofunctional compound as chain stopper or for forming endgroups. The backbone of the polyurethane elastomer or the TPU applied in present invention is typically linear. In an embodiment, the TPU has one or two endgroups, preferably one or two hydrophobic endgroups.

[0048] In embodiments, the polyurethane elastomer comprises hard blocks that include urethane groups and optionally urea groups in repeating units, which have resulted from reaction of a diisocyanate with a diol and optionally a diamine as chain extender.

[0049] Suitable diisocyanates include aromatic, aliphatic and cycloaliphatic compounds, having an average of 1.9-2.1 isocyanate groups per molecule. In an embodiment, the diisocyanate comprises 4,4’-diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate, 2,6-toluene diisocyanate (TDI), 1 ,4-phenylene diisocyanate, hexamethylene diisocyanate (HDI), tetramethylene- 1 ,4-diisocyanate, cyclohexane-1 ,4-diisocyanate, dicyclohexylmethane-4,4’- diisocyanate (HMDI), isophorone diisocyanate (IPDI), or a mixture thereof. In an embodiment, the diisocyanate comprises hexamethylene diisocyanate, dicyclohexylmethane 4,4’-diisocyanate, isophorone diisocyanate, or a mixture thereof. In an embodiment, the diisocyanate consists of hexamethylene diisocyanate, dicyclohexylmethane 4,4’-diisocyanate, isophorone diisocyanate, or a mixture thereof. In an embodiment, the diisocyanate comprises 4,4’-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, or 1 ,4-phenylene diisocyanate. In an embodiment, the diisocyanate consists of 4,4’-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1 ,4-phenylene diisocyanate, or a mixture thereof.

[0050] Chain extenders are typically low molar mass aliphatic compounds, having two or more hydroxyl or amine groups. Bifunctional chain extenders result in linear, generally thermoplastic polymers, whereas multifunctional isocyanates and / or chain extenders would lead to branched or cross-linked products. In an embodiment, the bifunctional chain extender has a molar mass of at least 60 g / mol, at least 70 g / mol, at least 80 g / mol, at least 90 g / mol, or at least 100 g / mol. In an embodiment, the chain extender has a molar mass of at most 500 g / mol, at most from 400 g / mol, at most 300 g / mol, at most 200 g / mol, or at most 150 g / mol. In an embodiment, the chain extender comprises ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1 ,3- propanediol, 1,4-butanediol, 1,5-pentanediol, 1 ,6-hexanediol, or 1,8-octanediol; and / or such corresponding diamines. In embodiments, the polyurethane elastomer comprises only diol chain extenders and shows thermoplastic behavior; that is the polyurethane elastomer is a thermoplastic polyurethane elastomer or TPU.

[0051] In other embodiments, the polyurethane elastomer comprises hard blocks having both urethane and urea linkages. The advantage thereof is enhanced interaction between the hard blocks, allowing a higher content of soft blocks resulting in block copolymers showing enhanced flexibility and elasticity, and excellent flex life or fatigue resistance. Depending on the ratio diol / diamine, the polyurethane elastomer may show such strong interaction that at a melt processing temperature thermal degradation may be such that solution processing is to be preferred for optimal performance. Commercially available examples of such polyurethane elastomers comprising both urethane and urea linkages DSM Biomedical Elasthane™ 55D Thermoplastic Polyether Polyurethane (TPU).

[0052] In further embodiments, the polyurethane elastomer comprises soft blocks derived from at least one aliphatic polymer diol or polyol, which is chosen from the group consisting of polyethers, polyesters, polyacrylates, polyolefins and polysiloxanes (also called silicones); which polymers are bifunctional with hydroxyl (or amine) terminal groups. Such polymer diols for the soft blocks are understood herein to include oligomers, homopolymers and copolymers, and polyesters are considered to include polycarbonates. Generally known polyurethane block copolymers and methods to prepare these copolymers are described in a.o. US4739013, US4810749, US5133742 and US5229431.

[0053] In embodiments of the present disclosure the polyurethane elastomer comprises as soft block at least one polymer diol chosen from an aliphatic polyester diol, an aliphatic polyether diol, a poly(isobutylene) diol and a polysiloxane diol. As for chain extenders, also amine-functional soft blocks can be used, resulting in additional urea linkages. Biocompatibility and biostability of such polyurethane block copolymers in the human body has been proven.

[0054] Mechanical and other properties of a polyurethane block copolymer can be tailored by varying chemical compositions and / or molar mass of the blocks. The hard blocks of a polyurethane elastomer for use in the invention may have a molar mass of about 160 to 10,000 Da, and more preferably of about 200 to 2,000 Da. The molar mass of the soft segments may be typically about 200 to 100,000 Da, and preferably at least about 400, 600, 800 or 1000 Da and at most about 10,000, 7500, 5000, 4000, 3000 or 2500 Da. Within the context of present disclosure, molar mass of polymers and oligomers discussed refers to the number average molar mass (Mn), as for example derived from GPC measurements. The ratio of soft to hard blocks can be chosen to result in certain stiffness or hardness of the polymer. Typically, hardness of the polyurethane as measured with the Shore durometer hardness test using A or D scales, may be from 40 ShA, or at least 50 or 60 ShA and up to 80, 75, 70, 65 or 60 ShD or up to 100, 90 or 85 ShA, generally representing a flexural modulus range of about 10 to 2000 MPa. In embodiments, the polyurethane elastomer has a hardness from 40 ShA to 60 ShD, preferably 40-100 ShA or 40-90 ShA.

[0055] In further embodiments of present invention, the polyurethane elastomer comprises an aliphatic polyether or an aliphatic polyester as soft block, more specifically an aliphatic polycarbonate. Suitable aliphatic polyethers include polypropylene oxide) diols, poly(tetramethylene oxide) diols, and their copolymers. Suitable aliphatic polyesters are generally made from at least one aliphatic dicarboxylic acid and at least one aliphatic diol, which components are preferably chosen such that an essentially amorphous oligomer or polymer is formed having a Tgbelow 10, 0, or -10 °C. Aliphatic polycarbonate diols are based on similar aliphatic diols as used for polyester diols, and can be synthesized via different routes as known in the art. Suitable examples include poly(hexamethylene carbonate) diols and poly(polytetrahydrofuran carbonate) diols. In an embodiment, the soft block is based on a poly(hexamethylene carbonate) diol, a poly(polytetrahydrofuran carbonate) diol, or a mixture thereof. In case the soft blocks of the polyurethane substantially consist of such polyols and contain no polysiloxane, the polymer has at least one hydrophobic endgroup, and preferably two hydrophobic endgroups.

[0056] In a further embodiment, the soft block comprises a polysiloxane diol such as a poly(dimethyl siloxane) diol, a polycarbonate diol, or a poly(tetramethylene oxide) diol. In an embodiment, the soft block is based on a polysiloxane diol, a polycarbonate diol, a poly(tetramethylene oxide) diol, or a mixture thereof. In an embodiment, the soft block comprises a mixture of two or more of a polysiloxane diol, a polycarbonate diol, or a poly(tetramethylene oxide) diol. In an embodiment, the soft block is based on a mixture of two or more of a polysiloxane diol, a polycarbonate diol, or a poly(tetramethylene oxide) diol. In an embodiment, the soft block comprises a polysiloxane diol and one or more of a polycarbonate diol and a poly(tetramethylene oxide) diol. In an embodiment, the soft block is based on a polysiloxane diol and one or more of a polycarbonate diol and a poly(tetramethylene oxide) diol.

[0057] In an embodiment, the soft blocks or the polymer diol may further comprise a C2-C16 fluoroalkyl diol or C2-C16 fluoroalkyl ether diol. In an embodiment, the soft block in the polyurethane backbone comprises the residue of 1 H,1 H,4H,4H-Perfluoro-1 ,4-butanediol, 1 H,1 H,5H,5H-Perfluoro-1 ,5-pentanediol, 1 H,1 H,6H,6H-perfluoro-1 ,6-hexanediol, 1 H,1 H,8H,8H- Perfluoro-1,8-octanediol, 1 H,1 H,9H,9H-Perfluoro-1,9-nonanediol, 1 H,1 H,10H,10H-Perfluoro- 1 ,10-decanediol, 1 H,1 H,12H,12H-Perfluoro-1,12-dodecanediol, 1 H,1 H,8H,8H-Perfluoro-3,6- dioxaoctan-1 ,8-diol, 1 H,1H,11 H,11 H-Perfluoro-3,6,9-trioxaundecan-1 ,11-diol, fluorinated triethylene glycol, or fluorinated tetraethylene glycol.

[0058] In an embodiment, the C2-C15 fluoroalkyl diol or C2-C16 fluoroalkyl ether diol has an Mnof at least 150 g / mol, at least 250 g / mol, or at least 500 g / mol. In an embodiment, the fluoroalkyl diol or fluoroalkyl ether diol has a molar mass of at most 1500 g / mol, at most 1000 g / mol, or at most 850 g / mol. In an embodiment, the C2-C16 fluoroalkyl diol or C2-C16 fluoroalkyl ether diol is present in an amount of at least 1 mass%, at least 2 mass%, or at least 5 mass%, based on the total mass of the polyurethane. In an embodiment, the C2-C16 fluoroalkyl diol or C2-C16 fluoroalkyl ether diol is present in an amount of at most 15 mass%, at most 10 mass%, or at most 8 mass%, based on the total mass of the polyurethane.

[0059] The polyurethane elastomer may comprise one or more hydrophobic endgroups. An endgroup is a generally a non-reactive moiety present at a terminal end of a molecule. In an embodiment, the polyurethane elastomer is linear and comprises a hydrophobic endgroup at one end or terminus, preferably at each terminus of the backbone; that is an average of about 2 endgroups. In an embodiment, the hydrophobic endgroup is a linear compound. In another embodiment, the hydrophobic endgroup is branched. An endgroup may have been formed by reacting a terminal isocyanate group present during or after forming the polymer backbone with a co-reactive group on a monofunctional compound or chain stopper. For instance, a formulation for forming a polyurethane may comprise a diisocyanate, a polymeric aliphatic diol, a chain extender, and a monofunctional compound; like 1 -octanol or octylamine to form a Cs alkyl endgroup.

[0060] In an embodiment, the hydrophobic endgroup comprises a C2-C20 alkyl, a C2-C16 fluoroalkyl, a C2-C16 fluoroalkyl ether, a hydrophobic poly(alkylene oxide) or a polysiloxane, including copolymers thereof. In an embodiment, the hydrophobic poly(alkylene oxide) is polypropylene oxide), poly(tetramethylene oxide) or a copolymer thereof. In an embodiment, the hydrophobic endgroup is a polysiloxane, like a poly(dimethyl siloxane). In an embodiment, the endgroup comprises C2-C20 alkyl, C2-C16 fluoroalkyl, C2-C16 fluoroalkyl ether, or a hydrophobic poly(alkylene oxide). Such endgroups may be formed with monofunctional alcohols, including carbinols, or amines of the foregoing. Such polyurethane elastomers having hydrophobic endgroups are found to positively affect properties of the polyurethane and its interaction with other materials, including other polymers like polyolefins and bodily tissue and fluid like blood.

[0061] In an embodiment, the hydrophobic endgroup comprises C2-C16 fluoroalkyl or C2-C16 fluoroalkyl ether. Such endgroups may be formed with monofunctional alcohols or amines comprising C2-C16 fluoroalkyl or C2-C16 fluoroalkyl ether. In an embodiment, the endgroup is formed from 1 H,1 H-Perfluoro-3,6-dioxaheptan-1-ol, 1H, 1 H-Nonafluoro-1 -pentanol, 1 H,1 H- Perfluoro-1 -hexyl alcohol, 1 H,1 H-Perfluoro-3,6,9-trioxadecan-1-ol, 1 H,1 H-Perfluoro-1-heptyl alcohol, 1H,1H-Perfluoro-3,6-dioxadecan-1-ol, 1 H,1 H-Perfluoro-1-octyl alcohol, 1 H,1 H-Perfluoro- 1-nonyl alcohol, 1 H,1 H-Perfluoro-3,6,9-trioxatridecan-1-ol, 1 H, 1 H-Perfluoro-1 -decyl alcohol, 1 H,1 H-Perfluoro-1-undecyl alcohol, 1 H,1 H-Perfluoro-1-lauryl alcohol, 1 H, 1 H-Perfluoro-1 -myristyl alcohol, or 1 H,1 H-Perfluoro-1-palmityl alcohol. In an embodiment, the hydrophobic endgroup is monomeric and has a molar mass of 200 g / mol or more, 300 g / mol or more, or 500 g / mol or more; and of 1,000 g / mol or less or 800 g / mol or less. In an embodiment, the endgroup is polymeric and has a molar mass of 10,000 g / mol or less, 8,000 g / mol or less, 6,000 g / mol or less, or 4,000 g / mol or less. In an embodiment, the endgroup is polymeric and has a molar mass of 500 g / mol or more, 1 ,000 g / mol or more, or 2,000 g / mol or more.

[0062] In an embodiment, the hydrophobic endgroup is present in an amount of at least 0.1 mass%, at least 0.2 mass%, at least 0.3 mass%, or at least 0.5 mass%, based on the total mass of the polyurethane. In an embodiment, the hydrophobic endgroup is present in an amount of at most 4 mass%, at most 3 mass%, at most 2 mass% or at most 1 mass%, based on the total mass of the polyurethane. In an embodiment, the hydrophobic endgroup is present in an amount of at least 0.1 mass%, at least 0.2 mass%, at least 0.3 mass%, or at least 0.5 mass%; and in an amount of at most 4 mass%, at most 3 mass%, at most 2 mass% or at most 1 mass%, based on the total mass of the polyurethane.

[0063] The hard blocks in such polyurethane or TPU are typically based on an aromatic diisocyanate like toluene diisocyanate (TDI) or methylenediphenyl diisocyanate (MDI), and a low molar mass aliphatic diol like 1 ,4-butanediol. Polyether and polycarbonate polyurethanes may be suitably used for biomedical applications, in view of their flexibility, strength, biostability, biocompatibility and wear resistance. A TPU containing a combination of a polyether and a polysiloxane or a polycarbonate and a polysiloxane, for example as the soft blocks, shows a unique combination of properties and may advantageously be used as the polyurethane in the coating. Commercially available examples of such polymers include CarboSil® TSPCU products (available from DSM Biomedical).

[0064] In a further embodiment, the polyurethane or TPU may be a blend of two or more polymers. In other embodiments the polyurethane or TPU may comprise one or more customary additives that are allowed for the targeted application. Examples of additives include stabilizers, anti-oxidants, processing aids, lubricants, surfactants, antistatic agents, colorants, radiopacifiers and fillers. The additives may be present in the typically effective amounts as known in the art, such as 0.01-30%, preferably 0.01-5 mass% based on the amount of the polyurethane, preferably 0.01-1 mass%. In another embodiment, the polyurethane or TPU substantially consists of polymer, and is substantially free of additives. Compounding

[0065] In an embodiment, the composition is formed by grafting the antimicrobial polymer onto the thermoplastic polymer by compounding. In an embodiment, the composition is formed by mixing a powder of antimicrobial polymer and thermoplastic polymer at elevated temperature. In an embodiment, the composition is formed by injection molding or extrusion. In an embodiment, a product is formed by injection molding or extrusion. In an embodiment, extrusion is used to create pellets or other intermediates that are then subsequently processed into medical devices or products.

[0066] According to an embodiment, the process for preparing the composition comprises the steps of: a) providing an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form, b) mixing the antimicrobial polymer of step a) and at least a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof, to form a mixture; c) heating the mixture, preferably to a temperature of from 180 °C to 250 °C; and d) cooling the mixture to thereby obtain the composition, wherein the composition comprises the antimicrobial polymer grafted onto the thermoplastic polymer.

[0067] The process of the present invention is performed preferably by extrusion. According to an embodiment, this is done using a single screw or twin-screw extruder which can either corotate or counter-rotate. However, it can also be done by kneading, melt-blending (solution blending. Optionally, the thermoplastic polymer and the antimicrobial polymer can be mixed before extrusion. The thermoplastic polymer should ideally also be dried to avoid introducing water into contact with the PHMG salt.

[0068] According to an embodiment, the process for preparing the composition comprises the steps of: a) providing an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form, b) mixing the antimicrobial polymer of step a) and at least a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof, to form a mixture; c) heating the mixture, preferably to a temperature of from 180 °C to 250 °C; d) extruding the mixture obtained in step c) through a die to form an extrudate; e) cooling the extrudate, in a water bath, and f) optionally, cutting or crushing the extrudate to form a product.

[0069] According to an embodiment, a dry powder blend of antimicrobial polymer and thermoplastic polymer is formed prior to compounding the antimicrobial polymer and thermoplastic polymer at elevated temperature. It was found that this dry powder blend may serve to further avoid water uptake by the hygroscopic PHMG salt.

[0070] Thus, in an embodiment, a process for preparing a composition comprises the steps of: a) providing an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form; b) mixing the antimicrobial polymer of step a) and a polymer powder comprising at least a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof, to form a mixture; c) heating the mixture, preferably to a temperature of from 180 °C to 250 °C; d) extruding the mixture obtained in step b) through a die to form an extrudate; e) cooling the extrudate, in a water bath, and f) optionally, cutting or crushing the extrudate to form a product.

[0071] According to an embodiment, the content of water of the mixture during step b) or after step b) is less than 200 ppm. According to an embodiment, the content of water of the mixture during step c) or after step c) is less than 200 ppm.

[0072] Further, in an embodiment, the composition comprises a mixture of a powder comprising the antimicrobial polymer and a powder comprising the thermoplastic polymer. In an embodiment, both powders have a particle size less than 10 mm, preferably less than 9 mm, preferably less than 8 mm, preferably less than 7 mm, preferably less than 6 mm, preferably less than 5 mm, preferably less than 4 mm, preferably less than 3 mm, preferably less than 2 mm.

[0073] According to an embodiment, the thermoplastic polymer is present at between 75% and 99%, preferably between 90 and 99%, based on the total weight, of the mixture in step b). In an embodiment of the processes the thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, styrene-ethylene-butylene-styrene (SEBS) copolymer, and mixtures thereof.

[0074] According to an embodiment, the amount of the polyhexamethylene guanidine salt is comprised between 1 and 25%, preferably between 1 and 10 %, based on the total weight of the mixture in step b). In an embodiment, the mixture has a water content of less than 300 ppm, preferably less than 200 ppm, more preferably less than 100 ppm. In an embodiment, the powder of the polyhexamethylene guanidine salt has a water content of less than 300 ppm, preferably less than 200 ppm, more preferably less than 100 ppm.

[0075] In an embodiment, the mixture consists of the powder comprising the polyhexamethylene guanidine salt and the powder comprising the thermoplastic polymer. In an embodiment, the mixture comprises a powder consisting of the polyhexamethylene guanidine salt and the powder consisting of the thermoplastic polymer. In an embodiment, the mixture consists of a powder consisting of the polyhexamethylene guanidine salt and the powder consisting of the thermoplastic polymer.

[0076] In step c) of the process, the mixture is heated at a temperature comprised preferably between 180 and 250 °C to obtain a molten state. In an embodiment, a blanket of nitrogen contacts the antimicrobial polymer prior to and / or during contact with the thermoplastic polymer.

[0077] During the extrusion process, in step d), the mixture is then forced through a die having an orifice with a predetermined diameter which ranges typically from about 1 to 4mm, However, much larger diameters for the die are also possible.

[0078] Finally, the mixture is cut at the temperature of the melt (for example thanks to a die face cutter). A cooling step (for example at ambient temperature) is typically performed either before or after the cutting step. A cooling bath or spray cooling can be used.

[0079] The extruder that can be used in the present invention is typically a twin-screw extruder. In general, the extruder consists of multiple barrel sections, which are independently temperature controlled. In one embodiment, the extruder comprises 2 to 9 heating and cooling zones with temperatures ranging from 180 to about 270 °C.

[0080] Additives

[0081] Different additives can be added in step c). By non-limiting examples, one may cite for examples stabilizers, anti-oxidants, processing aids, lubricants, surfactants, antistatic agents, colorants, radiopacifiers and fillers, and mixtures thereof.

[0082] According to an embodiment, the stabilizer can be added in an amount up to 3% based on the total weight of the mixture in step b). According to an embodiment, the antioxidant can be added in an amount up to 3% based on the total weight of the mixture in step b).

[0083] In an embodiment, the radiopacifier comprises tantalum, gold, platinum, tungsten, iridium, platinum-tungsten, platinum-iridium, palladium, rhodium, barium sulfate, bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, ionic or non-ionic contrasting agents such as diatrizoates, iodipamide, iohexyl, iopamidol, iothalamate, ioversol, ioxaglate, and metrizamide, or a combination thereof. In an embodiment, the radiopacifier comprises tantalum, gold, platinum, tungsten, or a mixture or alloy thereof. In an embodiment, the radiopacifier is present as particles. In an embodiment, the radiopacifier particles have an average particle diameter of at least 1 nm, preferably at least 5, 10, 25, 50, 100, or 200 nm. In an embodiment, the radiopacifier particles have an average particle diameter of at most 3 pm, preferably at most 2, 1 , 0.5, or 0.2 pm. Average particle diameter is measured using photon correlation spectroscopy (PCS) in accordance with ISO13321:1996. In an embodiment, the radiopacifier is surface treated with an adhesion promoter to enhance adhesion to the polyurethane; like with a glycidyl methacrylate (GMA) modified random ethylene / acrylate copolymer, or a GMA and maleic anhydride (MA) modified random ethylene / acrylate copolymer. The radiopacifier can be added in an amount up to 30% based on the total weight of the mixture in step b), for effective visualization in medical imaging techniques using x-rays or other radiation.

[0084] Product

[0085] Another aspect of the invention is a product. In an embodiment, the product is formed by the process defined as previously. In an embodiment, the product is a pellet or a filament. It should be understood that the product prepared by the present invention can be shaped in different forms. Indeed, it can be shaped into pellets or can be shaped directly into a tube forming a tubular device. In an embodiment, a medical device is placed in water to activate any endgroups after forming the medical device from the product.

[0086] Medical device

[0087] Another aspect of the invention is a medical device comprising or consisting of the composition as previously disclosed, or formed from the product as previously disclosed.

[0088] In the case that the medical device is formed from pellets, the medical device can be obtained by thermoforming the pellets via extrusion or injection molding or melt compression to obtain the medical device. In the event the product comprises tubing or the like, the product is or is part of the medical device. The medical device includes but is not limited to peripheral venous catheters; breathing tubes, stents; products for application in regional anesthesia, especially catheters, couplings, filters; products for infusion therapy, especially containers, ports, conduit systems, filters; accessories, such as connectors, spikes, valves, three-way stopcocks, syringes, conduits, injection ports; products of formulation, especially transfer sets, mixing sets; urological products, especially catheters, urine measuring and collecting devices; wound drains; wound dressing: Surgical Suture materials; implantation auxiliaries as well as implants, especially plastic implants, for example, hernia meshes, non-woven, knitwear / knitted fabrics, ports, port catheters, vascular protheses; disinfectants; disposable Surgical instruments; thoracic drains; probes; catheters; housings of medical devices, especially infusion pumps, dialysis devices and Screens; artificial dentures; containers for liquids, especially contact lens containers

[0089] According to an embodiment, the medical device is chosen from the group consisting of catheters, vascular access devices, peripheral lines, intravenous lines, gastric feeding tubes, guidewires, pacemakers.

[0090] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following exemplary embodiments and claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as” or “like”) provided herein, is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to practicing the invention.

[0091] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. While certain optional features are described as embodiments of the invention, the description is meant to encompass and specifically disclose all combinations of these embodiments unless specifically indicated otherwise or physically impossible.

[0092] The experiments and samples below further elucidate embodiments of the invention, but of course, should not be construed as in any way limiting the scope of the claims.

[0093] EXAMPLES

[0094] Example 1

[0095] Synthesis of polyhexamethylene guanidine hydrochloride salt (PHMG-HCI)

[0096] A 2-liter double walled glass reactor with an anchor stirrer and a stainless-steel lid, was equipped with a condenser, a nitrogen inlet and an outlet from which a tube lead the gasses into a beaker with 1.5 I of water. A stream of nitrogen was passed over the reactor during the first part of the reaction. Hexamethylendiamine was melted before use, guanidinium chloride was dried in vacuum (50 mbar, 70 °C, 24 hrs) before use. The reactor was charged with 460.5 g hexamethylenediamine (3.97 mol. To this was added 388.8g guanidine hydrochloride (4.07 mol). The reactor was warmed to 60 °C to melt the compounds. When part of the hexamethylenediamine has melted the stirrer was switched on and was set at 16 rpm. After 15 minutes the temperature was increased to 70 °C and the stirrer set at 50rpm. After another 15 minutes the temperature was further increased to 90 °C and the stirrer set at 100 rpm and stirring was continued for 3 hrs. After this the temperature was increased to 120 °C and the stirrer at 16 rpm. This stirrer speed was maintained throughout the rest of the reaction. After 3.5 hrs the temperature was increased further to 150 °C. After 30 minutes at 150 °C the pressure was reduced to 750 mbar. During the following 45minutes the pressure was gradually reduced to 150 mbar. After another 1 hr and 15 minutes the pressure was further reduced to 100 mbar. After stirring for 4 hrs at 150 °C the temperature was increased to 180°C. After 2.5 hrs at 180 °C the temperature was further increased to 205 °C. After 2 hrs and 15 minutes the pressure was reduced to 50 mbar and maintained for 1 hr and 15 minutes after which the heater and stirrer were switched off and the reaction mixture was left at room temperature overnight. The next day the temperature was set at 150 °C. After 45min the temperature was increased to 205 °C and the stirrer was set at 16 rpm. No vacuum was applied but a stream of nitrogen was passed over the reaction mixture. After 3 hrs and 15 min at 205 °C the heater and stirrer were switched off. After the temperature of the reaction mixture has reached 50 °C 500 ml ethanol was added to the reactor and warmed to reflux to dissolve the product. After 2 hrs refluxing the product had not dissolved. 200 ml additional ethanol was added the mixture was warmed to reflux. The polymer did not dissolve (completely). 500 ml water was added and the ethanol was distilled off. The product dissolved within 2 hrs.

[0097] The polymer solution was collected in PTFE trays and the majority of the solvent was allowed to evaporate at room temperature. The product was further dried in vacuum (70 mbar) at 70 °C. Yield 712 g (99%).

[0098] 1 H-NMR (D2O):1.22ppm (2H, broad signal, CH2-C-C-N), 1.44ppm (2H, broad signal, CH2-C-N), 2.59ppm (low intensity signal, 0.03H), 3.04ppm (2H, broad signal, CH2-N).

[0099] 13C-NMR (D2O): 25.55 (CH2-C-C-N), 28.01 ppm (CH2-C-N), 41.16ppm (CH2-N), 154.21 ppm (C=N), 155.61 ppm (C=N), 156.05ppm (C=N).

[0100] Example 2

[0101] Pellets preparation (compounding)

[0102] Compounding was done on an Xplore MIDI MC15HT midi extruder at 15 g scale. The midi extruder has a twin screw and a bypass. The nozzle is a two-way valve which can be switched to extrusion or on circulation of the melt through the bypass.

[0103] Polyurethane (Elasthane™ 55D) pellets and antimicrobial polymer powder from Example 1 were manually fed to the extruder with a plunger. The plunger was charged with part of the Elasthane™ 55D pellets. On top of that the antimicrobial polymer powder was added and the plunger was further filled with Elasthane™ 55D pellets. The plunger was manipulated multiple times in order to mix the pellets and powder. The mixed material was pressed in the extruder at operating temperature. The compound was mixed in the extruder for 5 or 3 minutes at 200 °C. After the mixing period the valve was opened and the extrudate collected in 300 ml of water.

[0104] Compositions with 1 wt%, 5 wt%, and 10 wt% PHMG-HCI were made. Blank material (thermoplastic polymer without antimicrobial polymer) was extruded as reference. Example 3

[0105] Thermoformed melt pressing of the pellets to obtain film(s)

[0106] Films of the compounds from Example 2 were pressed with the Fontijn Press Labpro 400 film press. After manual pelletizing of the extrudate, obtained in the compounding step, and drying in vacuum (50 mbar, 70 °C, 24 hrs) 3.2 g of the material was used to obtain films with a thickness of approx. 200 pm.

[0107] The mold was constructed as follows: From a metal sheet with 0.2 mm thickness a space was cut with 100 mm x 100 mm dimension. On top and bottom of the mold a PET foil (thickness 0.025 mm) with anti-adhesive layer was placed. The stack was placed between 2 metal plates. Pressing conditions:

[0108] Mold dimension LxWxH= 100 x 100 mm x 0.2 mm

[0109] Temperature top and bottom press plates 200 °C

[0110] The press was pre-heat to 200 °C. Films were pressed in a 2-step process.

[0111] Step 1 : 2 KN pressure, 200 °C, pre-melting for 5 minutes

[0112] Step 2: 150 KN pressure, 200 °C, melt and pressing for 5 minutes.

[0113] After pressing temperature was brought down by active cooling from 200 -> 40 °C under a pressure of 150 KN. When 40 °C was reached, the temperature was increased to 90 °C. The mold with the pressed film was taken from the press and immediately cooled in water. This simulates extrusion of tubular medical components.

[0114] Example 4

[0115] Antimicrobial studies

[0116] From the films obtained in Example 3, disks were punched with a diameter of 4 mm. The disks were sterilized and cleaned with 70% ethanol prior to testing.

[0117] The materials were tested for their antimicrobial properties against Escherichia coli, Staphylococcus aureus and Candida albicans. The test was performed according to the regulations of DIN EN ISO / IEC 17025 for testing and calibration laboratories. The test objects are incubated with cells of the test strain. Loose cell material that does not adhere to the test surface is removed in defined wash steps. The antimicrobial properties of the material are tested for 18 hours (challenge time) at 37 °C by tracking the ability of the bacteria on its surface to proliferate (multiply). The test results apply to measurements taken during this period. If all bacteria on the surface of the material are prevented from multiplying, no daughter cells are produced and the test object is considered bactericidal. Materials can also be antimicrobial, which means that not all cells on the test surface are prevented from growing. Some cells are able to divide and release daughter cells into the surroundings, which are then optically registered in a so-called growth curve. If surviving daughter cells are grown under controlled conditions over 48 h (observation time), a higher turbidity and therefore a bigger signal is generated. At the same time only vital and proliferative cells are accounted for. In particular antimicrobial samples will release daughter cells into the surrounding. Hence, microbial growth is first observed noticeably later. This right-shift towards longer times is indicative for the antimicrobial efficacy of the tested samples. The so- called onset OD serves as a quantifiable parameter and is equivalent to the required number of hours required for the surviving daughter cells to grow to a predefined optical density (OD = 0.2). Antimicrobial efficacy was measured in comparison to a non-antimicrobial blank sample. The value determined for the blank sample is subtracted from that of the actual sample (net onset OD). Internal controls that are present on all microplate assays serve as permanent monitors of the measuring process.

[0118] The material is regarded antimicrobial only if it inhibits the formation of at least 99.9% of the daughter cells during the observation period in comparison to the blank sample. The assessment criteria used to determine the antimicrobial efficacy are shown in Table 1.

[0119] Table 1 : Assessment Criteria for Antimicrobial Efficacy

[0120] The method for determination of antimicrobial efficacy has been adapted for Candida albicans. The definition when a material is considered antimicrobial (the formation of at least 99.9% of the daughter cells during the challenge time is prevented in comparison with the blank sample) was therefore adjusted to a minimum onset OD of 9 hours. Results are shown in Table 2. Table 2: Antimicrobial studies

[0121] Example 5

[0122] Leachable and extractables determination

[0123] Leachable and extractables determination from the extrudate (from the cooling water)

[0124] Extrudates from Example 2 that were collected in water, were evaporated to dryness and the residue was analysed by NMR in D2O with Na acetate as the internal standard. The peak at 3.1 ppm was used to determine whether there were any PHMG-HCI based extractables (see Figure 1).

[0125] One can see from Figure 2 that that there are no antimicrobial leachables by demonstrating that there are no PHMG-HCI -based extractables after compounding.

[0126] Leachable and extractables determination from the pellets (after the cutting step)

[0127] Pellets from Example 2 (10% of PHMG-HCI in Elasthane™ 55D) were submitted to extraction in D2O for 24 hrs at room temperature followed by 6 hrs at 37 °C. A reference Elasthane™ 55D underwent the same sequence.

[0128] In a 10 ml vial with screw cap, 1 g of the Elasthane™ and compounds was mixed with 5 g of D2O. The mixtures were placed on a horizontal roller at 25 rpm at room temperature. Samples were taken after 24 hrs mixing and analyzed with1H-NMR. After 24hrs at room temperature the mixtures were placed at 37”C for 6hrs at static conditions. A sample of the mixture was taken and analyzed with1H-NMR. NMR spectra were recorded on a Jeol 400 MHz, JNM-ECZL400S spectrometer, Routine1H-NMR spectra were recorded with a relaxation delay time of 1s.

[0129] Extraction spectrum of the pellets (10% of PHMG-HCI in Elasthane™ 55D) after 24 hrs at room temperature is shown in Figure 3.

[0130] It can be concluded from Figure 3 (and based on Figure 1 , spectrum of PHMG-HCI and) that, with1H-NMR, no extracted PHMG-HCI (peak at 3.1 ppm - see Figure 1) could be detected from the pellet after 24 hrs at room temperature. Similar results have been observed for extrudates at different concentrations (5 and 10% of PHMG-HCI) and also after an additional 6 hours at 37 °C for all 3 concentrations.

[0131] This example has shown that none of the polymers are leaching from the extrudates from the cooling water (nor dry pellets) which is a key requirement for cardiovascular applications.

[0132] Furthermore, it has shown that the cooling water used during the extrusion process does not contain any PHMG-HCI extractables, avoiding any risk linked to the aquatoxicity.

[0133] Example 6

[0134] Process Comparison

[0135] The compounding was performed according to the method described in Example 2.

[0136] The following comparative compositions were prepared:

[0137] C1. Elasthane™ 55D (no antimicrobial polymer - anhydrous process)

[0138] C2. Elasthane™ + 5 wt% water (no anti-microbial polymer - water-doped process)

[0139] E3. Elasthane™ + 5 wt% PHMG-HCI (antimicrobial polymer - anhydrous process)

[0140] C4. Elasthane™ + 5% wt% PHMG-HCI added as 50 wt% solution in water (compounding composition with 5 wt% PHMG-HCI, 5 wt% water) (antimicrobial polymer - water-doped process)

[0141] Sheets were pressed according to the method described in Example 3. The anhydrous process involves substantially complete drying of the components prior to extrusion. The water-doped process also involves substantially complete drying of the polyurethane, and adding the stated amount of water. Example 7

[0142] Sample characterization

[0143] Dogbones were cut from the pressed films with a length of 20 mm and a width of the narrow part of 4 mm with a Zwick press, according to ISO 527-1 :2019. Tensile tests were performed according to ISO 527-1:2019 on a Zwick Z010 tensile tester equipped with a 100N compressed air clamp. The clamps were modified with 60D Shore hardness cushions to prevent sample damage. Double sided TESA adhesive tape was used to prevent slippage of the sample during testing.

[0144] Table 3 shows the results of molecular weight analysis and mechanical testing of the compounds with and without antimicrobial compounds and compounding with and without water.

[0145] Table 3: Molecular weight of Elasthane™ and tensile data on Elasthane™ with and without PHMG-HCI.

[0146] * PHMG-HCI added as a 50 wt% solution in water

[0147] When looking at thermally processed Elasthane™, comparing in water and thermal processing dry, a reduction of Mw of 29 % can be observed. In the presence of the antimicrobial polymer (PHMG-HCI) and with the same thermal processes, there is a more significant loss in molecular weight. When processing in water, a 30% Mw loss is observed compared to a 19% Mw loss when prepared under dry conditions. Table 4: Tensile parameters

[0148] It can be seen from Table 4 that, when processing Elasthane™ on its own in water, there is a deterioration (25%) in stress at break in comparison to process it under dry conditions. It can also be seen that in the presence of the antimicrobial polymer, processing in water gives a 30 % reduction in stress at break. Surprisingly, the reduction of the stress at break for composition according to the invention (dry conditions) is minimal (5 %).

[0149] Example 8

[0150] Milling of PHMG-HCI or TPU

[0151] PHMG-HCI synthesized as in Example 1 or TPU was loaded into a Wiley Mill hopper and the mill was allowed to reach 1200 rpm. The hopper was open and the material was slowly fed into the mill. As the PHMG-HCI or TPU was milled it was fed through a 2 mm mesh through and the resultant powder collected.

[0152] Example 9

[0153] Dry powder blending

[0154] The powders formed in Example 8 were placed in stainless pans and dried in a Yamamoto Vacuum Oven set at 80 °C for 24 hrs prior to compounding. For each compounding run, 1 kg charges were blended as follows. Dry TPU and PHMG-HCI powders were transferred from their respective drying stainless pans into 16 X 20 mm resealable polybags used for blending. Each quantity of TPU and PHMG-HCI were weighed on the digital scale to ensure the accuracy of the required 1 %, 5 %, and 10 % blends of PHMG-HCI and TPU. The bags were manually tumbled for a minimum of 30 seconds to achieve a thorough blend of powders. Example 10

[0155] Extrusion of TPU and PHMG-HCI to produce filaments

[0156] Compounding and filament extrusion was conducted on a Eurolab 16 mm twin screw extruder fitted with a Brabender / or Thermo Fischer material feeder and a Brabender water bath. A nitrogen line was connected to the hopper on the feeder to ensure a blanket of nitrogen would prevent the blended TPU and PHMG-HCI from picking up any moisture from the ambient air.

[0157] The extruder barrel and die heat zones were turned on and allowed to reach their respective setpoints. As the setpoints were reached, the barrel and die were permitted to soak heat for at least 30 minutes. Once the soak time was reached, the screw rotation speed was set and the screw motor tuned on. Once the extruder screws began to rotate, the feeder speed was set, and the feeder tuned on. The process settings used for each compounding run are shown in Table 5.

[0158] Table 5: Compounding Settings

[0159] Once material extruded from the strand die, it was manually advanced through the water bath and into the pelletizer or extruded filaments were isolated for testing.

[0160] Filaments having a diameter of 7 + / - 1 mm were obtained.

[0161] Example 11

[0162] Anti-microbial testing of produced filaments

[0163] CarboSil® 2080A was used as the TPU. The filaments were produced according to Examples 8-

[0164] 10 and ETO sterilized. The sterilized filaments were then submitted for antimicrobial testing. Antimicrobial testing was conducted as described in Example 4.

[0165] # one of the four test specimens tested as antimicrobial, but three did not show sufficient antimicrobial activity.

[0166] E. Coli presents a specific challenge for this test because of its high replication rate. CarboSil® containing 10 wt% PHMG-HCI demonstrates antimicrobial properties potentially suitable for commercial applications. Further process optimization may result in samples with adequate antimicrobial activity at concentrations below 5 wt% PHMG-HCI.

[0167] Example 12

[0168] Comparison of feeding antimicrobial polymer and TPU directly into a feeder separately versus as a dry, preblended powder

[0169] Sample Preparation and Extrusion

[0170] This comparison involves powder / powder dry blends or separate feeding of PHMG-HCI and TPU powders. The TPU is CarboSil® 2080A or Elasthane™ 55D. For these experiments, a 10 wt% PHMG-HCI sample was prepared. Powders were prepared as in Example 8. All experiments were conducted in 15 g batches. Sample preparation and extrusion were carried out in a fume hood or a well-ventilated space.

[0171] Part A: Dry Blend and Extrusion

[0172] 13.5 g of thermoplastic polymer (powder) was weighed into the container and 1 .5 g of PHMG- HCI powder added. The container was removed from the scale and securely closed with a cap. It was then shaken for approximately 1 minute to produce a well-mixed dry blend. Prior to mixing, it was ensured that the container was properly sealed to prevent material loss. The dry blend was carefully transferred into a feeder on an Xplore MC 15HT with 1.5 mm nozzle. The loading opening of the feeder was covered with a cap to avoid moisture absorption by the PHMG-HCI. Extrusion occurred at 200 °C at 150 rpm. When the extruder was ready for operation rotation of the screw was started. When 150 rpm was reached, the feeder was started and the dosing time was recorded from the moment material started falling into the funnel until no further material came out of the feeder. When dosing was done, both feeders were stopped simultaneously, and the compound was mixed for 1 min. After 1 min the tapping valve was opened and the extrudate was caught in a scotch bottle containing ~100ml of room temperature demineralized water.

[0173] Part B: Preparation and extrusion for Separate Feeding

[0174] Funnels and transport screws of the feeder were dismantled and thoroughly cleaned. The feeder components were reassembled. Prior to operation, the output of the feeder at various speed settings was determined to establish the correct settings for dosing the required amount of material within a specific time frame.

[0175] For the thermoplastic polymer, the appropriate settings were identified to dose 13.5 g of thermoplastic polymer in 1 min. It was noted that different thermoplastic polymers and their physical states (granules or powder) influenced the dosing rate, so the output was determined separately for each variant.

[0176] For the PHMG-HCI during testing and feeding the loading opening from the feeder was covered with parafilm to limit moisture absorption. Since it was only in powder form, output had only to be determined once for dosing 1.5 g in 1 min.

[0177] A ZD 5 FB-C-1M Three Tec feeder and the included feeder on the Xplore MC 15HT were each loaded with a different powder and output was determined. The feeders were run slowly until material came out of the feeders then placed carefully above the funnel of the extruder.

[0178] Extrusion occurred at 200 °C and 150 rpm. When the extruder was ready for operation, rotation of the screw was started. When 150 rpm was reached, both feeders were started simultaneously and run for 1 min. When dosing was complete, both feeders were stopped simultaneously and the compound mixed for 1 min. After 1 min the tapping valve was opened and the extrudate was caught in a scotch bottle containing ~100ml of room temperature demineralized water.

[0179] The filamentous extrudates prepared pre dry blending (Part A) and in situ mixing (Part B) were compared in the extruder. The results show that with pre-blending of dry powders there is avoidance of bubbles that arise from rapid moisture uptake that the inventors attribute to the hygroscopic nature of PHMG-HCI. See Fig. 4.

[0180] Example 13

[0181] Comparison of leachables

[0182] Samples formed in accordance with Example 12 (10 wt% PHMG-HCI and 90 wt% TPU) were extracted in ethanol. Approximately 1 g of each sample was weighed into a vial and 10 mL of solvent (~7 g) was added, fully submerging them. Then, the vials were put into a water bath at 50 °C for 72 hours. After the 72 hours, the extracts were measured by LC-UV-MS.

[0183] Quantification was performed by extracting the 200 nm UV signal and by external calibration with reference PHMG solutions, in different concentrations. The reported PHMG concentration is calculated relative to the sample, taking into account the dilution factor.

[0184] The results are shown in the below table.

[0185] A comparison of the leachables and extractables from the extruded filaments prepared according to Example 12 showed lower PHMG-HCI extractables when extruding a dry blend in accordance with Part A of Example 12 vs. via separate hoppers in accordance with Part B of Example 12. The effect is present when varying the TPU, but more pronounced for the thermoplastic silicone polycarbonate polyurethane.

Claims

SET OF CLAIMS1 . A process for preparing a composition comprising the steps of: a) providing an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form; b) mixing the antimicrobial polymer of step a) and a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, styrene-ethylene-butylene-styrene (SEBS) copolymer, and mixtures thereof, to form a mixture; and c) shaping the mixture obtained in step b).

2. The process according to claim 1 , wherein the step of shaping comprises the steps of: c1) heating the mixture, preferably to a temperature of from 180 °C to 250 °C; c2) extruding the mixture obtained in step c) through a die to form an extrudate; c3) cooling the extrudate, optionally in a water bath, and c4) optionally, cutting or crushing the extrudate to form a product.

3. A process for preparing a composition comprising the steps of: a) providing a mixture comprising an antimicrobial polymer, wherein the antimicrobial polymer comprises a polyhexamethylene guanidine salt in a dry powder form, and a polymer powder comprising at least a thermoplastic polymer chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof; b) heating the mixture to a temperature of from 180 °C to 250 °C; and c) cooling the mixture to form a composition.

4. The process according to any one of the preceding claims, wherein the thermoplastic polymer is chosen from the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, and mixtures thereof.

5. The process according to any one of the preceding claims, wherein the content of water of the antimicrobial polymer is less than 200 ppm.

6. The process according to any one of the preceding claims, wherein the content of water of the mixture is less than 200 ppm.

7. The process according to any one of the preceding claims, wherein the particle size of the polyhexamethylene guanidine salt is less than 3 mm.

8. The process according to any one of the preceding claims, wherein the polyhexamethylene guanidine salt is chosen from the group consisting of a chloride salt, iodide salt, bromide salt, fluoride salt, phosphate (PO4) salt, sulfonate salt, carboxylate salt, stearate salt, and a mixture thereof.

9. The process according to claim 8, wherein the polyhexamethylene guanidine salt is polyhexamethylene guanidine hydrochloride salt.

10. The process according to any one of the preceding claims, wherein the thermoplastic polymer is a polyurethane.

11. The process according to any one of the preceding claims, wherein the amount of the thermoplastic polymer is between 75% and 99%, preferably between 90% and 99% of the total weight of the mixture.

12. The process according to any one of the preceding claims, wherein the amount of the polyhexamethylene guanidine salt is between 1 and 25%, preferably between 1 and10% of the total weight of the mixture.

13. The process according to any one of the preceding claims, wherein the thermoplastic polymer is in a dry powder form and has a particle size of less than 3 mm.

14. A mixture comprising: a) from 1 to 25%, preferably from 1 to 10%, based on the total weight of the mixture, of a powder comprising a polyhexamethylene guanidine salt having a particle size of less than 5 mm, more preferably less than 4 mm, more preferably less than 3 mm, more preferably less than 2 mm;b) from 75 to 99%, preferably from 90 to 99%, based on the total weight of the mixture, of a powder comprising a thermoplastic polyurethane having a particle size of less than 5 mm, more preferably less than 4 mm, more preferably less than 3 mm, more preferably less than 2 mm; wherein the water content of the mixture is less than 300 ppm, preferably less than 200 ppm, more preferably less than 100 ppm.

15. A pellet obtained by the process according to any one of claims 1 to 13 or formed by extruding the mixture of claim 14.

16. A medical device formed by extruding a plurality of pellets according to claim 15.

17. The medical device according to claim 16, chosen from the group consisting of catheters, vascular access devices, peripheral lines, intravenous lines, gastric feeding tubes, guidewires, and pacemakers.

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